Sub-optimal disease management for respiratory illnesses, e.g. asthma, cystic fibrosis, and chronic obstructive pulmonary disease (COPD) collectively represents about billion dollar worldwide market for biotechnology-derived proteins. The pulmonary delivered protein, represent an enormous market opportunity for pulmonary drug delivery. The delivery of drugs via inhalation for local delivery to the upper lung (most commonly in the form of metered-dose inhalers) and for systemic delivery (into the bloodstream) via the deep lung defines the scope of pulmonary drug delivery, is the subject of intense research.
For more than a decade, companies have searched extensively to find a drug delivery technology which is patient-friendly, non-invasive, and an economically viable alternative to injecting the large macromolecule proteins. Some of the earliest efforts involved transdermal delivery via electroporations but this has mostly been abandoned as large molecules simply can't pass through the skin. Oral delivery, which would clearly be the preferable dosage form, has had some success, but a major obstacle is the degradation and denaturization of proteins in the gastrointestinal tract.
Drug delivery through the lung appears optimal for two major reasons, i.e. the enormous surface area available for delivery, and permeability to large molecules. The lung has about a half billion alveoli. The alveoli in an average adult lung have a surface area the size of a tennis court, far exceeding the surface area of most other delivery routes, e.g. GI tract, by several orders of magnitude. The alveoli allow oxygen and other molecules to readily pass into the circulatory system. Conventional metered dose inhalers, primarily used for asthma, deliver drugs into the upper branches of the lung. In terms of permeability, the buccal cavity and lung are ideal absorption areas for both small and large molecules. Large proteins, including antibodies, are readily absorbed through the alveoli either directly into the circulatory system or, more frequently, via the lymphatic system, which subsequently releases the drug into the bloodstream.
The ability to deliver large molecule drugs orally, e.g. buccally, and/or into the deep lung will represent one of the most significant technical breakthroughs in drug delivery.
New products that address these drug delivery needs are sought, which simultaneously provide patients with a convenient user friendly mechanism and physicians with a tool to improve therapy, compliance, and to prevent or reduce expensive hospital stays.
Oral delivery offers a variety of benefits for systemic drug delivery. For example, it provides easy, non-invasive access to a permeable mucosa, which facilitates rapid drug absorption and a fast onset of action of the drug. In comparison to the GI tract and other organs, the buccal environment has lower enzymatic activity and a neutral pH.
The absorption of proteins and peptides is believed to be enhanced by the diffusion of large molecules entrapped in droplet form through the aqueous pores and the cell structure perturbation of the tight paracellular junctions. In order to further improve the penetration and absorption of formulation it has now been found that such formulations can be mixed with a propellant (preferably a non-CFC) and delivered, e.g. applied to the buccal mucosa, through metered dose inhalers (MDIs) or similar. The present invention uses novel formulations that are intended to improve the quality (in terms of absorption), stability, and performance of MDI-delivered pharmaceuticals. A novel method is used to solubilize drugs in a propellant. The formulation ingredients are selected specifically to give enhancement in the penetration through the pores and facilitate the absorption of the drugs to reach therapeutic levels in the plasma.
With previous formulations, in order to administer the pharmaceutical agent, it is necessary to shake the vial in order to temporarily intimately mix the two phases, so that a mixture of pharmaceutical formulation and propellant are expelled from the vial upon opening a dosing valve. The propellant and pharmaceutical phases quickly separate after shaking. Separation of the phases may lead to situations wherein the person administering the drug does not shake the vial sufficiently, forgets to shake the vial or waits too long before opening the dosing valve. Such situations lead to a lack of uniformity in the amount of pharmaceutical being administered from one opening of the valve to the next, i.e. from "shot" to "shot". This is particularly problematic where the amount of pharmaceutical agent to be administered is critical, e.g. with insulin and some pain killing drugs and narcotics. It is desirable, therefore, for the formulation and propellant to be evenly mixed, e.g. as a solution, stable suspension or the like.
The present invention is directed to providing a stable mixture of propellant and pharmaceutical agent.
The terms "comprising" and "comprises" when used in this specification are taken to specify the presence of the stated features, integers, steps or components but do not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.
The term "solubilized" is used in this specification to refer to a stable intimate mixture of ingredients. It has not been determined whether the mixture is a solution, suspension or other form of intimate mixture. Such a solubilized mixture is stable for substantial periods of time, e.g. months, without separation.